Novel antitumoral use of cabazitaxel

ABSTRACT

The invention relates to a compound of formula:which may be in base form or in the form of a hydrate or a solvate, in combination with prednisone or prednisolone, for its use as a medicament in the treatment of prostate cancer, particularly metastatic prostate cancer, especially for patients who are not catered for by a taxane-based treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/743,411, filed Jan. 15, 2020, which is a continuation of U.S.application Ser. No. 15/627,962, filed Jun. 20, 2017, which is acontinuation of U.S. application Ser. No. 14/575,566, filed Dec. 18,2014, which is a continuation of U.S. application Ser. No. 13/456,720,filed Apr. 26, 2012, which is a continuation of InternationalApplication No. PCT/1132010/054866, filed Oct. 27, 2010, which claimsthe benefit of priority of U.S. Provisional Application No. 61/256,160,filed Oct. 29, 2009, U.S. Provisional Application No. 61/293,903, filedJan. 11, 2010, U.S. Provisional Application No. 61/355,834, filed Jun.17, 2010, U.S. Provisional Application No. 61/355,888, filed Jun. 17,2010, U.S. Provisional Application No. 61/369,929, filed Aug. 2, 2010,U.S. Provisional Application No. 61/383,933, filed Sep. 17, 2010, andU.S. Provisional Application No. 61/389,969, filed Oct. 5, 2010, all ofwhich are incorporated herein by reference.

The present invention relates to a novel antitumoral use of cabazitaxelin the treatment of prostate cancer, which may be metastatic, especiallyfor patients who are not catered for by a taxane-based treatment. Inparticular, the present invention relates to the use of cabazitaxel inthe treatment of patients with castration resistant metastatic prostatecancer, who have been previously treated with a docetaxel based regimen,an unmet medical need.

BACKGROUND

Prostate cancer affects a large proportion of the male populationworldwide: 680 000 cases worldwide in 2002; it is predicted that therewill be 900 000 new cases per year up to 2010 (CA Cancer J. Clin., 2005,55, 74-108). It is the most frequently occurring cancer in men afterlung cancer.

Prostate cancer is generally treated at the start by depriving theandrogenic hormones, i.e. by surgical excision of the testicles TheCurrent State of Hormonal Therapy for Prostate Cancer CA Cancer J.Clin., May 2002; 52: 154-179, or by radiotherapy treatment External beamradiation therapy for prostate cancer CA Cancer J. Clin., November 2000;50: 349-375. Treatments with antiandrogens or hormone manipulations areassociated with responses of short duration and without any improvementin the survival time.

The use of cytotoxic chemotherapy is not a routine treatment, whereasits role in alleviating the symptoms and reducing the levels of PSA(prostate-specific antigen) is established. No monotherapy has obtaineda degree of response of greater than 30%; combinations with an effect onPSA levels were tested. No effect on the survival time was seen and,what is more, the toxicity of these treatments, particularly on elderlypatients, is problematic since, in addition to their tumour, they aregenerally suffering from related health problems and have a limitedreserve of bone marrow.

Until recently, the chemotherapies used were limited tocyclophosphamide, anthracyclines (doxorubicin or mitoxantrone) andestramustine, and the effects of these treatments are relativelymediocre. Palliative effects were observed in patients following theadministration of corticoids alone or of mitoxantrone with eitherprednisone or hydrocortisone. Following Phase II trials, the combinationof mitoxantrone with corticoids was recognized as the referencetreatment for hormone-resistant prostate cancer. More recently,treatments with docetaxel in combination with estramustine or prednisonehave made it possible to treat cancers that are resistant to hormonedeprivation Advances in Prostate Cancer Chemotherapy: A New Era BeginsCA Cancer J. Clin., September 2005; 55: 300-318, the survival wasimproved by 2.4 months.

It is generally accepted that the responses in advanced prostate cancersare difficult to evaluate on account of the heterogeneity of the diseaseand the lack of consensus regarding the treatment response criteria.Many patients with metastatic prostate cancer have no measurabledisease, but have symptoms dominated by bone metastases. Measurement ofthe PSA level has been found to be a means for evaluating novelcandidates and also the measurement of the tumour when this is possible,the measurement of bone tumours, the quality of life and the measurementof the pain.

Furthermore, cancer may become resistant to the agents used, inparticular to taxanes, which limits the possible treatment options.Several taxane resistance mechanisms have been described (expression ofP-glycoprotein P-gp, mdr-1 gene, modified metabolism of taxane, mutationof the tubulin gene, etc.): see Drug Resistance Updates 2001, 4(1), 3-8;J. Clin. Onc. 1999, 17(3), 1061-1070.

The technical problem that the invention intends to solve is that ofproviding a novel therapeutic option for treating prostate cancer,especially for patients who are not catered for by a taxane-basedtreatment, such as patients with castration resistant metastaticprostate cancer who have been previously treated with docetaxel (soldunder the brand name Taxotere®) based regimen, an unmet medical need.

Four clinical trials on cabazitaxel are known since April 2006. Threemonotherapy tests have made it possible to determine the maximumtolerated dose and the toxicities at the limit doses: these tests wereperformed on breast, sarcoma and prostate tumours. Doses of 10-30 mg/m²every three hours were used. A phase II trial was performed on patientswith a breast cancer, who had previously received taxanes andanthracyclines as adjuvant (i.e. after a surgery) or as a first-linetreatment. The response levels were 14.6% as adjuvant and 9.5% assecond-line treatment.

SUMMARY

The invention relates to a novel antitumoral pharmaceutical therapeuticuse comprising cabazitaxel of formula

The invention also relates to methods of treating patients with prostatecancer comprising administering an effective amount of the antitumoralagent cabazitaxel to said patient.

This antitumoral agent may be in the form of anhydrous base, a hydrateor a solvate, intended for treating prostate cancer, in particular fortreating patients who are not catered for by a taxane-based treatment,such as patients who have been previously treated with a docetaxel-basedregimen. This compound is preferably administered to a patient withadvanced metastatic disease. In particular, the compound is administeredto a patient with castration resistant prostate cancer. Cabazitaxel ispreferably administered in combination with a corticoid chosenespecially from prednisone and prednisolone. This corticoid ispreferably administered at a daily dose of 10 mg orally.

In some aspects of the invention, cabazitaxel is administered incombination with prednisone for its use as a medicament in the treatmentof patients with hormone-refractory prostate cancer who have beenpreviously treated with docetaxel based regimen.

In some aspects of the invention, cabazitaxel is administered at a dose(defined for each administration) of between 20 and 25 mg/m².Cabazitaxel may be in the form of an acetone solvate. More particularly,the acetone solvate of cabazitaxel contains between 5% and 8% andpreferably between 5% and 7% by weight of acetone.

In some aspects of the invention, cabazitaxel may be administered byintravenous infusion at a dose of between 15 and 25 mg/m², thisadministration cycle of the antitumour agent being repeated at aninterval of 3 weeks between each cabazitaxel administration, whichinterval may be prolonged by 1 to 2 weeks depending on the tolerance tothe preceding cabazitaxel administration.

In some embodiments, the effective amount of cabazitaxel produces atleast one therapeutic effect selected from the group consisting ofincrease in overall survival, partial response, reduction in tumor size,reduction in metastasis, complete remission, partial remission, stabledisease, or complete response.

The present invention also relates to a pharmaceutical composition thattreats patients with prostate cancer comprising a clinically proven safeand effective amount of cabazitaxel.

Further embodiments of the invention comprise methods or using,treating, promoting, and providing cabazitaxel.

The present invention also relates to packages and articles ofmanufacture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays the Kaplan-Meier curves of the overall survival in acabazitaxel study.

FIG. 2 displays the Kaplan-Meier curves of progression-free survival ina cabazitaxel study.

FIG. 3 shows an intention-to-treat analysis of overall survival insubgroups of patients defined by baseline characteristics. Hazardratios<1 favor the cabazitaxel group, while those >1 favor themitoxantrone group. CI denotes confidence intervals.

FIG. 4 graphically depicts the proportion of patients with changes inECOG performance status from baseline during treatment (safetypopulation). The “Improved” column represents PS2 at baseline changed to0 or 1 during treatment. The “stable” column represents no change, andthe “Worse” column represents PS2 at baseline and changed to ≥3, or 0 or1 at baseline changed to ≥2 during treatment.

FIG. 5 graphically depicts the proportion of patients with changes frombaseline in the Present Pain Intensity score during treatment (ITT). The“Improved” column represents patients in which the PPI score duringtreatment was lower versus baseline. The “Stable” column represents nochange, and the “Worse” column represents patients with >1 unit increasein PPI score during treatment versus baseline.

FIG. 6 graphically presents the mean area under the curve for PPI andanalgesic scores by treatment cycle.

FIG. 7 graphically presents the mean AUC analgesic score.

DETAILED DESCRIPTION Definitions

-   -   Effective amount, as used herein, means an amount of a        pharmaceutical compound, such as cabazitaxel, that produces an        effect on the cancer to be treated.    -   Clinically proven, as used herein, means clinical efficacy        results that are sufficient to meet FDA approval standards.    -   Castration resistant prostate cancer, as used herein, is        synonymous with hormone-refractory prostate cancer.    -   “Patient,” as used herein, includes both human and animals. In        one embodiment, a patient is a human.

Cabazitaxel belongs to the taxoid family and has the formula:

The chemical name of cabazitaxel is4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonyl-amino-2-hydroxy-3-phenylpropionate.Cabazitaxel is synonymously known as(2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-ylbenzoate.

This compound and a preparative method thereof is described in WO96/30355, EP 0 817 779 B1 and U.S. Pat. No. 5,847,170, which are herebyincorporated herein by reference. Cabazitaxel may be administered inbase form (cf. above formula), or in the form of a hydrate. It may alsobe a solvate, i.e. a molecular complex characterized by theincorporation of the crystallization solvent into the crystal of themolecule of the active principle (see in this respect page 1276 of J.Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetonesolvate, and, more particularly, may be the solvate described in WO2005/028462. It may be an acetone solvate of cabazitaxel containingbetween 5% and 8% and preferably between 5% and 7% by weight of acetone(% means content of acetone/content of acetone+cabazitaxel×100). Anaverage value of the acetone content is 7%, which approximatelyrepresents the acetone stoichiometry, which is 6.5% for a solvatecontaining one molecule of acetone. The procedure described below allowsthe preparation of an acetone solvate of cabazitaxel:

940 ml of purified water are added at 20±5° C. (room temperature) to asolution of 207 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl propionate atabout 92% by weight in about 2 litres of acetone, followed by seedingwith a suspension of 2 g of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate isolatedfrom acetone/water in a mixture of 20 ml of water and 20 ml of acetone.The resulting mixture is stirred for about 10 to 22 hours, and 1.5litres of purified water are added over 4 to 5 hours. This mixture isstirred for 60 to 90 minutes, and the suspension is then filtered underreduced pressure. The cake is washed on the filter with a solutionprepared from 450 ml of acetone and 550 ml of purified water, and thenoven-dried at 55° C. under reduced pressure (0.7 kPa) for 4 hours. 197 gof4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl(2R, 3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate acetonecontaining 0.1% water and 7.2% acetone (theoretical amount: 6.5% for astoichiometric solvate) are obtained.

Cabazitaxel may be administered parenterally, such as via intravenousadministration. A galenical form of cabazitaxel suitable foradministration by intravenous infusion is that in which the cabazitaxelis dissolved in water in the presence of excipients chosen fromsurfactants, cosolvents, glucose or sodium chloride, etc. For example, agalenical form of cabazitaxel may be prepared by diluting a premixsolution of cabazitaxel contained in a sterile vial (80 mg ofcabazitaxel+2 ml of solvent+Polysorbate 80) with a sterile vialcontaining a solution of 6 ml of water and ethanol (13% by weight of 95%ethanol) in order to obtain 8 ml of a solution ready to be rediluted ina perfusion bag. The concentration of cabazitaxel in thisready-to-redilute solution is about 10 mg/ml. The perfusion is thenprepared by injecting the appropriate amount of this ready-to-redilutesolution into the perfusion bag containing water and glucose (about 5%)or sodium chloride (about 0.9%).

Cabazitaxel may be administered in combination with a corticoid, such asprednisone or prednisolone, as two distinct pharmaceutical preparations.

Accordingly, one aspect of the invention is a method of treatingprostate cancer comprising administering to a patient in need thereof aneffective amount of cabazitaxel in combination with a corticoid, such asprednisone or prednisolone.

The combination is administered repeatedly according to a protocol thatdepends on the patient to be treated (age, weight, treatment history,etc.), which can be determined by a skilled physician. In one aspect ofthe invention, cabazitaxel is administered by perfusion to the patientaccording to an intermittent program with an interval between eachadministration of 3 weeks, which may be prolonged by 1 to 2 weeksdepending on the tolerance to the preceding administration. The mediannumber of cycles is 6. The prednisone or prednisolone may beadministered daily, for example in the form of one dosage intake perday, throughout the duration of the treatment. Examples of doses for thetwo antitumoral agents are given in the “Example” section. The currentlyrecommended dose is 25 mg/m² of cabazitaxel administered as a on-hourinfusion and 10 mg per day of prednisone or prednisolone administeredorally.

In some aspects of the invention, the patient to be treated has prostatecancer that is resistant to hormone therapy (i.e., hormone refractory)and has previously been treated with docetaxel. In some aspects, thepatient has prostate cancer that progressed during or after treatmentwith docetaxel. In some aspects, the patient was previously treated withat least 225 mg/m² cumulative dose of docetaxel. In a particular aspect,the patient showed progression of their disease in the six monthsfollowing hormone therapy or during docetaxel treatment or afterdocetaxel treatment. In another particular aspect, the patient showedprogression of their disease in the three months following hormonetherapy or after docetaxel treatment.

In some aspects of the invention, the patient to be treated has ameasurable tumour and may show progression of the disease via ametastatic lesion of the viscera or of a soft tissue of at least 1 cmdetermined by MRI or by an axial tomographic scan (CT scan).

In some aspects of the invention, the patient to be treated has anunmeasurable tumour and may show an increase in the PSA level with threemeasurements at a 1-week interval or the appearance of new lesions.

In some aspects of the invention, the patient to be treated hasundergone castration by orchidectomy or with LHRH agonists, eliminationof the androgens or monotherapy with estramustine.

In a preferred aspect, the life expectancy of the patient to be treatedshould be at least 2 months.

In some aspects, the treatment does not include patients who havepreviously received mitoxantrone, or who have received less than 225mg/m² of docetaxel, or who have undergone a radiotherapy that haseliminated more than 40% of the marrow, who have received a treatmentwithin the 4 weeks preceding the test, who have a neuropathy or astomatitis, involving the brain or the meninges, who have shown severehypersensitivity to polysorbate or to prednisone, whose blood analysisshows an appreciable decrease in neutrophils, haemoglobin or platelets,an increase in bilirubin and/or liver enzymes and creatinine, or whohave heart problems or an infection requiring antibiotics.

An aspect of the invention comprises increasing the survival of apatient with hormone refractory metastatic prostate cancer, comprisingadministering a clinically proven effective amount of cabazitaxel to thepatient in combination with prednisone or prednisolone. In a particularaspect, the patient has previously been treated with adocetaxel-containing regimen.

Cabazitaxel may be administered in combination with a medication toprevent or control nausea and vomiting or to prevent or controlhypersensitivity to the cabazitaxel treatment. Preferably, a patient ispre-medicated with the medication, for example, at least 30 minutesprior to administering each dose of cabazitaxel.

One aspect of the invention comprises a method of reducing the risk of asevere hypersensitivity reaction in a patient with prostate cancer beingtreated with cabazitaxel, comprising administering to the patient amedication to prevent hypersensitivity prior to the administration ofcabazitaxel.

Severe hypersensitivity reactions to cabazitaxel can occur and mayinclude generalized rash/erythema, hypotension and bronchospasm.Patients should be observed closely for hypersensitivity reactions,especially during the first and second infusions. Hypersensitivityreactions may occur within a few minutes following the initiation of theinfusion of cabazitaxel, thus facilities and equipment for the treatmentof hypotension and bronchospasm should be available. If severehypersensitivity reaction occurs, cabazitaxel infusion should beimmediately discontinued and appropriate therapy should be administered.Examples of medications which may be used to prevent hypersensitivity tothe cabazitaxel treatment include antihistamines, such asdexchloropheniramine (for example 5 mg), and diphenhydramine (forexample 25 mg) or equivalent antihistamines; and corticosteroids, suchas dexamethasone (for example 8 mg) or an equivalent steroid.

Nevertheless, cabazitaxel should not be given to and may becontraindicated in patients who have a history of severehypersensitivity reactions to cabazitaxel. Depending on the formulationadministered, cabazitaxel may also be contraindicated in patients whohave a history of hypersensitivity reactions to other drugs formulatedwith polysorbate 80.

One aspect of the invention comprises an article of manufacturecomprising:

-   -   a) a packaging material;    -   b) cabazitaxel, and    -   c) a label or package insert contained within the packaging        material indicating that severe hypersensitivity reactions can        occur.

Gastrointestinal symptoms, such as, for example nausea, vomiting, anddiarrhea, may occur with the treatment of cabazitaxel. Mortality relatedto diarrhea and electrolyte imbalance has been reported. Therefore,patients may also be rehydrated and treated with anti-diarrheal oranti-emetic medications as needed. Treatment delay or dosage reductionmay be necessary if patients experience Grade 3 diarrhea.

Accordingly, the methods of the invention include administering amedication to prevent hypersensitivity or a medication to prevent orcontrol nausea and vomiting in combination with cabazitaxel.

Examples of medications which may be used to prevent or control nauseaand vomiting include histamine H2 antagonists and antiemetics, such asondansetron, granisetron and dolesetron.

A possible side effect of the treatment with cabazitaxel is neutropenia,which is characterized by a reduced number of neutrophils.Unfortunately, a number of neutropenia deaths have been reported.Therefore, frequent blood counts should be obtained or performed tomonitor for neutropenia. If neutropenia occurs, cabazitaxel treatmentmay be discontinued, and restarted when neutrophil counts recover to alevel of >1,500/mm³. Cabazitaxel should not be given to a patient with aneutrophil count≤1,500 cells/mm³.

The present invention therefore also relates to a method of treatingprostate cancer with cabazitaxel comprising administering cabazitaxel tothe patient, monitoring blood counts in the patient, and measuringneutrophil levels. In one aspect, the method further comprisesdiscontinuing cabazitaxel treatment if neutropenia occurs, andoptionally restarting cabazitaxel treatment when neutrophil countsrecover to a level of >1,500/mm³. In one aspect, the monitoringcomprises taking a blood sample from the patient.

Determining neutrophil counts can be performed according to procedureswell know to those skilled in the art.

One aspect of the invention is a method of reducing the risk ofneutropenia complications comprising administering cabazitaxel incombination with an agent useful for treating neutropenia. Such aneutropenia treatment agent is, for example, a hematopoietic growthfactor which regulates the production and function of neutrophils suchas a human granulocyte colony stimulating factor, (G-CSF). In aparticular aspect of the invention, the neutropenia is complicatedneutropenia. Complicated neutropenia includes febrile neutropenia,prolonged neutropenia, or neutropenic infection. In a preferredembodiment, the neutropenia treatment agent is administered prior to theadministration of cabazitaxel.

A particular aspect of the invention comprises a method of reducing therisk of neutropenia complications in a patient with prostate cancerbeing treated with cabazitaxel, comprising monitoring blood counts inthe patient at regular intervals during treatment of the patient withcabazitaxel; reducing the dose of cabazitaxel if the patient experiencesfebrile neutropenia or prolonged neutropenia; discontinuing cabazitaxeltreatment if the patient's neutrophil count is ≤1,500 cells/mm³; andoptionally restarting cabazitaxel treatment when the patient'sneutrophil counts recover to a level≥1,500 cells/mm³.

In a particular aspect, primary prophylaxis with G-CSF should beconsidered in patients with high-risk clinical features (age>65 years,poor performance status, previous episodes of febrile neutropenia,extensive prior radiation ports, poor nutritional status, or otherserious co-morbidities) that predispose them to increased complicationsfrom prolonged neutropenia. Therapeutic use of G-CSF and secondaryprophylaxis should be considered in all patients considered to be atincreased risk for neutropenia complications.

In another aspect, the monitoring of complete blood counts is performedon a weekly basis during cycle 1 and before each treatment cyclethereafter so that the dose can be adjusted, if needed. Therefore,another aspect for reducing the risk of neutropenia complicationscomprises monitoring blood counts in the patient and adjusting the doseof cabazitaxel. An example of a dose modification is described inExample 2.

One aspect of the invention comprises an article of manufacturecomprising:

-   -   a) a packaging material;    -   b) cabazitaxel, and    -   c) a label or package insert contained within the packaging        material indicating that cabazitaxel should not be given to        patients with neutrophil counts of ≤1,500 cells/mm³.

Cases of renal failure should be indentified and managed aggressively,accordingly to procedures known to those skilled in the art. Renalfailure may be associated with sepsis, dehydration, or obstructiveuropathy. Furthermore, impaired hepatic function (e.g., totalbilirubin≥ULN, or AST and/or ALT≥1.5×ULN) may increase cabazitaxelconcentrations, and cabazitaxel should not be given to patients withhepatic impairment.

Cabazitaxel may cause fetal harm when administered to a pregnant woman.

Prednisone or prednisolone administered at 10 mg daily does not affectthe pharmacokinetics of cabazitaxel.

Cabazitaxel is primarily metabolized through CYP3A. Concomitantadministration of strong CYP3A inhibitors (for example, ketoconazole,itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) mayincrease cabazitaxel concentrations. Therefore co-administration ofcabazitaxel with strong CYP3A inhibitors should be avoided. Cautionshould be exercised with concomitant use of moderate CYP3A inhibitors.One aspect of the invention is a method of treating a patient forprostate cancer comprising determining whether the patient is undergoingtreatment with a CYP3A inhibitor, discontinuing treatment with a CYP3Ainhibitor, and then administering cabazitaxel to the patient.

Concomitant administration of strong CYP3A inducer (e.g., phenytoin,carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) maydecrease cabazitaxel concentrations. Therefore co-administration ofcabazitaxel with strong CYP3A inducers should be avoided. Therefore, oneaspect of the invention is a method of treating a patient for prostatecancer comprising determining whether the patient is undergoingtreatment with a CYP3A inducer, discontinuing treatment with a CYP3Ainducer, and administering cabazitaxel to the patient.

In addition, patients should also refrain from taking St. John's Wort.

In some aspects of the invention, the cabazitaxel is administered in anamount to provide an AUC of about 991 ng·h/mL (CV 34%).

In some aspects of the invention, the cabazitaxel is administered in anamount to provide an C_(max) of about 226 ng·h/mL (CV 107%).

In some aspects of the invention, the cabazitaxel is administered in anamount to provide a plasma clearance of 48.5 L/h (CV 39%).

One aspect of the invention is a package comprising cabazitaxel and alabel, in a position which is visible to prospective purchasers,comprising a printed statement which informs prospective purchasers thatthe mean C_(max) of cabazitaxel in patients with metastatic prostatecancer was 226 ng/mL (CV 107%).

Another aspect of the invention is a package comprising cabazitaxel anda label, in a position which is visible to prospective purchasers,comprising a printed statement which informs prospective purchasers thatthe mean AUC of cabazitaxel in patients with metastatic prostate cancerwas 991 ng·h/mL (CV 34%).

Another aspect of the invention is a package comprising cabazitaxel anda label, in a position which is visible to prospective purchasers,comprising a printed statement which informs prospective purchasers thatcabazitaxel has a plasma clearance of 48.5 L/h (CV 39%).

A variety of educational materials may be employed to ensure properprescribing, dispensing, and patient compliance according to the methodsdescribed herein. For example, a variety of literature and othermaterials, such as, for example, prescribing information, packageinserts, medications guides, physician information sheets, healthcareprofessional information sheets, medical journal advertisements, andproduct websites may describe the risks and benefits of takingcabazitaxel.

The invention also concerns a package comprising cabazitaxel and alabel, said label comprising one or more messages that:

-   -   a) the efficacy and safety of cabazitaxel in combination with        prednisone were evaluated in patients with hormone refractory        metastatic prostate cancer previously treated with a docetaxel        containing regimen; or    -   b) a total of 755 patients were randomized to receive either        cabazitaxel 25 mg/m³ every 3 weeks for a maximum of 10 cycles        with prednisone mg orally daily, or to receive mitoxantrone 12        mg/m² intravenously every 3 weeks for a maximum of 10 cycles        with prednisone 10 mg orally daily; or    -   c) the median number of cycles was 6 in the cabazitaxel group        and 4 in the mitoxantrone group.

The invention also concerns a package comprising cabazitaxel and alabel, said label comprising one or more messages that:

-   -   a) neutropenic deaths have been reported; or    -   b) frequent blood counts should be obtained to monitor for        neutropenia; or    -   c) cabazitaxel should not be given if neutrophil counts are        ≤1,500 cells/mm³.

The invention also concerns a method of promoting the use of cabazitaxelthe method comprising the step of conveying to a recipient at least onemessage selected from:

-   -   a) neutropenic deaths have been reported; or    -   b) frequent blood counts should be obtained to monitor for        neutropenia; or    -   c) cabazitaxel should not be given if neutrophil counts are        ≤1,500 cells/mm³;    -   d) severe hypersensitivity can occur; or    -   e) severe hypersensitivity can occur and may include generalized        rash/erythema, hypotension and brochospasm; or    -   f) discontinue cabazitaxel immediately if severe reactions        occur; or    -   g) discontinue cabazitaxel immediately if severe reactions occur        and administer appropriate therapy; or    -   h) cabazitaxel is contraindicated in patients with a history of        severe hypersensitivity reactions to cabazitaxel or drugs        formulated with polysorbate 80.

The invention also concerns a method of providing cabazitaxel, whereinsaid cabazitaxel is provided along with information indicating that:

-   -   a) neutropenic deaths have been reported; or    -   b) frequent blood counts should be obtained to monitor for        neutropenia; or    -   c) cabazitaxel should not be given if neutrophil counts are        ≤1,500 cells/mm³;    -   d) severe hypersensitivity can occur; or    -   e) severe hypersensitivity can occur and may include generalized        rash/erythema, hypotension and brochospasm; or    -   f) discontinue cabazitaxel immediately if severe reactions        occur; or    -   g) discontinue cabazitaxel immediately if severe reactions occur        and administer appropriate therapy; or    -   h) cabazitaxel is contraindicated in patients with a history of        severe hypersensitivity reactions to cabazitaxel or drugs        formulated with polysorbate 80.

Example 1

A clinical study was performed wherein patients received eithertreatment with cabazitaxel or the reference treatment based onmitoxantrone each combined with prednisone or prednisolone.

More specifically, patients over 18 years of age with metastaticcastration resistant metastatic prostate cancer either measurable byRECIST criteria or non-measurable disease with rising PSA levels orappearance of new lesions, ECOG (Eastern Cooperative Oncology Group)performance stage 0-2, and adequate organ function (patients had to haveneutrophils>1,500 cells/mm³, platelets>100,000 cells/mm³, hemoglobin>10g/dL, creatinine<1.5× upper limit of normal (ULN), totalbilirubin<1×ULN, AST<1.5×ULN, and ALT<1.5×ULN) who had had prior hormonetherapy, chemotherapy, and radiotherapy, but had progressive during orafter docetaxel treatment (cumulative dose≥225 mg/m²) were randomized to10 mg/day of prednisone with either mitoxantrone 12 mg/m² or cabazitaxel25 mg/m², both administered every 3 weeks.

Patients with a history of congestive heart failure, or myocardialinfarction within the last 6 months, or patients with uncontrolledcardiac arrhythmias, angina pectoris, and/or hypertension were notincluded in the study.

720 patients were planned to be included in the clinical study: 360 ineach cabazitaxel+prednisone and mitoxantrone+prednisone group. Sevenhundred and fifty-five patients (755) (median age 68; 84% white) wereactually enrolled, 378 in the cabazitaxel and prednisone/prednisolonegroup and 377 in the mitoxantrone and prednisone/prednisolone group. Themaximal number of treatment cycles was 10 for cabazitaxel and 10 formitoxantrone. The median number of treatment cycles was 6 forcabazitaxel and 4 for mitoxantrone. The median prior dose of docetaxeltreatment was 576 mg/m² for the cabazitaxel group and 529 mg/m² for themitoxantrone group. Median follow-up was 12.8 months.

The measurements of the results are performed via the same tests as atinclusion. MRI and spiral computed tomographic (CT) scans are preferablyused.

The results are evaluated according to the following criteria (cf RECISTguideline):

-   -   overall survival (OS): the time from inclusion to the study to        the date of death    -   complete response (CR): disappearance of the lesions    -   partial response (PR): at least 30% reduction of the largest        diameter of the lesion    -   progression (PD): at least 20% increase in the sum of the        largest diameter of the lesion or appearance of one or more new        lesions    -   stable disease (SD): reduction of the tumour insufficient to be        included in PR and increase of the tumour insufficient to be        included in PD.

The confirmations of the measurements are made at least 4 weeks afterthe response criterion has been established for the first time.

The progression-free survival (PFS) is the time from inclusion in thestudy and the date of progression or death when the progression iseither an increase of the PSA, or of the tumour, or of the pain.

It was found that the combination of cabazitaxel and prednisone is awell-tolerated combination with the safety profile of taxanes. At thedose investigated in this trial (LD2: 25 mg/m² cabazitaxel+10 mg/m²/dayprednisone), patients receiving cabazitaxel demonstrated statisticallysignificant longer overall survival (OS) compared to mitoxantrone(p<0.0001). The hazard ratio was 0.70 (95% CI. 0.59, 0.83) in favor ofcabazitaxel corresponding to a 30% reduction in risk of death. Themedian survival for patients in the cabazitaxel group was 15.1 months incomparison to 12.7 months in the mitoxantrone group. Notably, theextension of survival was observed irrespective of ECOG performancestatus, number of prior chemotherapy regimens and age. Benefit was alsoseen in the third of patients who were docetaxel-refractory and hadprogressed during docetaxel therapy.

The data related to the treated patients are given in Table 1:

TABLE 1 Efficacy analysis (intention-to-treat) CbzP MP N = 378 N = 377Median Median (months) (months) Overall survival Median (months) 15.112.7 Hazard ratio (95% CI) 0.70 (0.59; 0.83) p-value¹ 0.0001 PFS Median(months) 2.8 1.4 Hazard ratio (95% CI) 0.74 (0.64-0.86) p-value¹ 0.0001Tumor response rate 14.4% 4.4% p-value² 0.0005 Time to Tumor Progression8.8 5.4 Median (months) p-value <0.001 PSA Response rate 39.2% 17.8%p-value² 0.0002 PSA PFS Median (months) 6.4 3.1 Hazard ratio (95% CI)0.75 (0.63-0.90) p-value¹ 0.0010 Pain Response rate 9.2% 7.8% p-value²0.6526 Pain PFS Median (months) Not 11.1 reached Hazard ratio (95% CI)0.91 (0.69-1.19) p-value¹ 0.5192 ¹Log-rank test, ²Chi-square test CbzP:cabazitaxel with prednisone MP: mitoxantrone with prednisone

Progression free survival (PFS) defined as the earliest progression intumor, PSA or pain was also statistically significantly longer in thecabazitaxel group compared to the mitoxantrone group (p<0.0001, hazardratio=0.74 (95% CI, 0.64, 0.86), and the median progression-freesurvival was 2.8 months versus 1.4 months. Response rates and PFS forPSA and tumor assessments were statistically significant in favor ofcabazitaxel, while response rate and PFS for pain did not show astatistically significant difference.

The most frequent Grade 3/4 toxicities were neutropenia observed with ahigher frequency in the cabazitaxel group with 81.7% compared to themitoxantrone group with 58.0%. Rates of febrile neutropenia were 7.5% inthe cabazitaxel group and 1.3% in the mitoxantrone group.

The most common 20%) grade 1-4 adverse reactions were anemia,leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea,vomiting, asthenia, and constipation.

The most common 5%) grade 3-4 adverse reactions in patients who receivedcabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia,diarrhea, fatigue, and asthenia.

Subgroup analyses by risk factors and a multivariate analysis showedthat OS outcomes were consistent and robust in favor of cabazitaxel asshown in the herebelow table:

TABLE 2 MP CbzP Median OS Median OS CbzP vs MP N (%) (mos) N (%) (mos)HR (95% CI) ITT 377 (100) 12.7 378 (100) 15.1 0.70 (0.59-0.83) PD whileon D 103 (27) 12.0 113 (30) 14.2 0.65 (0.47-0.90) PD after last 180 (48)10.3 158 (42) 13.9 0.70 (0.54-0.90) D dose, ≤3 mos PD after last 91 (24)17.7 103 (27) 17.5 0.78 (0.53-1.14) D dose, >3 mos mos = months D =Docetaxel

TABLE 3 Incidence of Reported Adverse Reactions¹ and HematologicAbnormalities in ≥5% of Patients Receiving cabazitaxel in Combinationwith Prednisone or Mitoxantrone in Combination with PrednisoneCabazitaxel 25 mg/m² every Mitoxantrone 12 mg/m² every 3 weeks withprednisone 3 weeks with prednisone 10 mg daily n = 371 10 mg daily n =371 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 n (%) n (%) n (%) n (%) AnyAdverse Reaction Blood and Lymphatic System Disorders Neutropenia² 347(94%) 303 (82%) 325 (87%) 215 (58%) Febrile Neutropenia 27 (7%) 27 (7%)5 (1%) 5 (1%) Anemia² 361 (98%) 39 (11%) 302 (82%) 18 (5%) Leukopenia²355 (96%) 253 (69%) 343 (93%) 157 (42%) Thrombocytopenia² 176 (48%) 15(4%) 160 (43%) 6 (2%) Cardiac Disorders Arrhythmia³ 18 (5%) 4 (1%) 6(2%) 1 (<1%) Gastrointestinal Disorders Diarrhea 173 (47%) 23 (6%) 39(11%) 1 (<1%) Nausea 127 (34%) 7 (2%) 85 (23%) 1 (<1%) Vomiting 83 (22%)6 (2%) 38 (10%) 0 Constipation 76 (20%) 4 (1%) 57 (15%) 2 (<1%)Abdominal Pain⁴ 64 (17%) 7 (2%) 23 (6%) 0 Dyspepsia⁵ 36 (10%) 0 9 (2%) 0General Disorders and Administration Site Conditions Fatigue 136 (37%)18 (5%) 102 (27%) 11 (3%) Asthenia 76 (20%) 17 (5%) 46 (12%) 9 (2%)Pyrexia 45 (12%) 4 (1%) 23 (6%) 1 (<1%) Peripheral Edema 34 (9%) 2 (<1%)34 (9%) 2 (<1%) Mucosal Inflammation 22 (6%) 1 (<1%) 10 (3%) 1 (<1%)Pain 20 (5%) 4 (1%) 18 (5%) 7 (2%) Infections and Infestations UrinaryTract Infection⁶ 29 (8%) 6 (2%) 12 (3%) 4 (1%) Pneumonia⁷ 12 (3%) 9 (2%)4 (1%) 3 (<1%) Investigations Weight Decreased 32 (9%) 0 28 (8%) 1 (<1%)Metabolism and Nutrition Disorders Anorexia 59 (16%) 3 (<1%) 39 (11%) 3(<1%) Dehydration 18 (5%) 8 (2%) 10 (3%) 3 (<1%) Musculoskeletal andConnective Tissue Disorders Back Pain 60 (16%) 14 (4%) 45 (12%) 11 (3%)Arthralgia 39 (11%) 4 (1%) 31 (8%) 4 (1%) Pain in Extremity 30 (8%) 6(2%) 27 (7%) 4 (1%) Muscle Spasms 27 (7%) 0 10 (3%) 0 Bone Pain 19 (5%)3 (<1%) 19 (5%) 9 (2%) Musculoskeletal Pain 18 (5%) 2 (<1%) 20 (5%) 3(<1%) Nervous System Disorders Peripheral Neuropathy⁸ 50 (13%) 3 (<1%)12 (3.2%) 3 (<1%) Dysgeusia 41 (11%) 0 15 (4%) 0 Dizziness 30 (8%) 0 21(6%) 2 (<1%) Headache 28 (8%) 0 19 (5%) 0 Renal and Urinary TractDisorders Hematuria 62 (17%) 7 (2%) 13 (4%) 1 (<1%) Dysuria 25 (7%) 0 5(1%) 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 43 (12%)4 (1%) 16 (4%) 2 (<1%) Cough 40 (11%) 0 22 (6%) 0 Skin and SubcutaneousTissue Disorders Alopecia 37 (10%) 0 18 (5%) 0 Vascular DisordersHypotension 20 (5%) 2 (<1%) 9 (2%) 1 (<1%) Median Duration of 6 cycles 4cycles Treatment ¹Graded using NCI CTCAE version 3 ²Based on laboratoryvalues, cabazitaxel: n = 369, mitoxantrone: n = 370. ³Includes atrialfibrillation, atrial flutter, atrial tachycardia, atrioventricular blockcomplete, bradycardia, palpitations, supraventricular tachycardia,tachyarrhythmia, and tachycardia. ⁴Includes abdominal discomfort,abdominal pain lower, abdominal pain upper, abdominal tenderness, and GIpain. ⁵Includes gastroesophageal reflux disease and reflux gastritis.⁶Includes urinary tract infection enterococcal and urinary tractinfection fungal. ⁷lncludes bronchopneumonia, lobar pneumonia, andpneumonia klebsiella. ⁸Includes peripheral motor neuropathy andperipheral sensory neuropathy.

TABLE 4 Patient Characteristics MP (n = 377) CBZP (n = 378) Age (years)Median [range] 67 [47-89] 68 [46-92] ≥65 (%) 57.0 64.9 ECOG PS (%) 0, 191.2 92.6 2 8.8 7.4 PSA* (ng/mL) Median [range] 127.5 [2-11220] 143.9[2-7842] Measurability of disease (%) Measurable 54.1 53.2Non-measurable 45.9 46.8 Disease site (%) Bone 87.0 80.2 Lymph node 44.845.0 Visceral 24.9 24.9 Pain at Baseline, 168 (44.6) 174 (46.0) no. (%)Previous Therapy, no. (%) Hormonal 375 (99.5) 375 (99.2) No. ofChemotherapy Regimens 1 268 (71.1) 260 (68.8) 2 79 (21.0) 94 (24.9) >230 (8.0) 24 (6.3) Radiation 222 (58.9) 232 (61.4) Surgery 205 (54.4) 198(52.4) Biologic Agent 36 (9.5) 26 (6.9) Previous docetaxel regimens, n(%) 1 327 (86.7) 316 (83.6) 2 43 (11.4) 53 (14.0) >2 7 (1.9) 9 (2.4)Median total previous 529.2 576.6 docetaxel dose (mg/m²) Diseaseprogression relative to docetaxel administration, n (%) During treatment104 (27.6) 115 (30.4) <3 months from last 181 (48.0) 158 (41.8) dose ≥3months from last 90 (23.9) 102 (27.0) dose Unknown 2 (0.5) 3 (0.8)Median time from last 0.7 0.8 docetaxel dose to disease progression(months)

The primary reason for treatment discontinuation in both groups wasdisease progression (Table 5). The median delivered relative doseintensity was 96.1% in the cabazitaxel group and 97.3% in themitoxantrone group. In the cabazitaxel group, >75% of patientsreceived >90% of the planned dose intensity. Overall, 5.1% ofmitoxantrone treatment courses were dose reduced compared with 9.8% ofcabazitaxel treatment courses; 6.3 and 7% of all treatment courses weredelayed by 9 days or less, and 1.6 and 2.3% of courses were delayed bymore than 9 days for mitoxantrone and cabazitaxel respectively (SeeTable 5).

TABLE 5 Treatment Received and Reasons for Discontinuation in theIntention-to-Treat Population.* Mitoxantrone Cabazitaxel (N = 377) (N =378) Patients receiving study 371 (98.4) 371 (98.1) treatment, no. (%)Patients completing 46 (12.2) 105 (27.8) planned ten cycles of studytreatment, no. (%) Discontinuation of study 325 (86.2) 266 (70.4)treatment, no. (%) Reasons for discontinuation of study treatment, no.(%) Disease progression 267 (70.8) 180 (47.6) Adverse event 32 (8.5) 67(17.7) Non-compliance with protocol 0 1 (0.3) Lost to follow-up 2 (0.5)0 Patient's request 17 (4.5) 8 (2.1) Other 7 (1.9) 10 (2.7) No. oftreatment cycles, 4 (1-10) 6 (1-10) median (range)^(†) Relative doseintensity, 97.3 (42.5-106.0) 96.1 (49.0-108.2) median % (range)^(†)Treatment delays, no. of cycles (%) ^(‡) ≤9 days 110 (6.3) 157 (7.0) >9days 28 (1.6) 51 (2.3) Dose reductions, no. of 88 (5.1) 221 (9.8) cycles(%) ^(‡)

The results of this study are further illustrated to FIGS. 1, 2, and 3.

Example 2

Table 6 illustrates an example of a dosage modification for adversereactions in patients treated with cabazitaxel

TABLE 6 Toxicity Dosage Modification Prolonged grade ≥3 Delay treatmentuntil neutrophil count neutropenia (greater is >1,500 cells/mm³, thenreduce dosage of than 1 week) despite cabazitaxel to 20 mg/m². Use G-CSFfor appropriate medication secondary prophylaxis. including G-CSFFebrile neutropenia Delay treatment until improvement or resolution, anduntil neutrophil count is >1,500 cells/mm³, then reduce dosage ofcabazitaxel to 20 mg/m². Use G-CSF for secondary prophylaxis. Grade ≥3diarrhea or Delay treatment until improvement or persisting diarrhearesolution, then reduce dosage of despite appropriate cabazitaxel to 20mg/m². medication, fluid and electrolytes replacement

Discontinue cabazitaxel treatment if a patient continues to experienceany of these reactions at 20 mg/m².

Example 3

Performance Status and Pain Scores during Treatment

Methods

-   -   ECOG PS, pain measures, and analgesic consumption were assessed        prior to every treatment cycle and at the end of study        treatment.    -   Pain assessments: Present Pain Intensity (PPI) scale from the        McGill-Melzack questionnaire (Melzack R. Pain 1975; 1:277-99).        Mean Analgesic Score (AS) derived from analgesic consumption (in        morphine equivalents) was calculated for the one-week period        prior to each evaluation. Area under the curve (AUC) of PPI and        AS was calculated by the trapezoid formula. Cumulative AUC of        PPI and AS was calculated up to the last cycle of data available        for each patient. Average AUC of the treatment groups was        compared from Cycle 1 to Cycle 10.

Results

-   -   Performance status remained stable in most patients during the        treatment period and was similar between groups. See FIG. 4.    -   Overall, PPI scores were comparable; improving from baseline in        21.3% of men in the CbzP group and 18.2% in the MP group. See        FIG. 5.    -   The CbzP group had a lower mean area under the curve (AUC) of        PPI, suggesting less severe pain especially during cycles 7-10.        See FIG. 6.    -   Analgesic use was comparable between the groups (lower mean AUC        of AS means lower pain medication use). See FIG. 7.

Conclusion

Despite longer treatment with CbzP no worsening in ECOG PS was seen.

Present Pain Intensity score improved in 21% of men in CbzP vs. 18% inMP arm.

Assessment of pain scores suggested less severe pain in the CbzP groupduring treatment.

Pain medication use was similar between groups.

Example 4

A population pharmacokinetic analysis was conducted in 170 patients withsolid tumors at doses ranging from 10 to 30 mg/m² weekly or every 3weeks.

Based on the population pharmacokinetic analysis, after an intravenousdose of cabazitaxel 25 mg/m² every 3 weeks, the mean C_(max) in patientswith metastatic prostate cancer was 226 ng/m L (CV 107%) and was reachedat the end of the 1-hour infusion (T_(max)). The mean AUC in patientswith metastatic prostate cancer was 991 ng·h/mL (CV 34%). No majordeviation from the dose proportionality was observed from 10 to 30 mg/m²in patients with advanced solid tumors. The volume of distribution (Vss)was 4,864 L (2,643 L/m² for a patient with a median BSA of 1.84 m²) atsteady state.

Based on the population pharmacokinetic analysis, cabazitaxel has aplasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m² for a patient with amedian BSA of 1.84 m²) in patients with metastatic prostate cancer.Following a 1-hour intravenous infusion, plasma concentrations ofcabazitaxel can be described by a 3-compartment PK model with α-, β-,and γ-half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

What is claimed is:
 1. A method for treating prostate cancer in apatient in need thereof comprising administering to said patient acompound of formula

which may be in base form or in the form of a hydrate or a solvate, incombination with prednisone or prednisolone.
 2. The method according toclaim 1, where the treated patients are not catered for by ataxane-based treatment.
 3. The method according to claim 1, where thepatients treated have been previously treated with a docetaxel-basedregimen.
 4. The method according to claim 1, where the prostate canceris an advanced metastatic disease.
 5. The method according to claim 1,where the prostate cancer is a castration resistant prostate cancer orhormone-refractory prostate cancer.
 6. The method according to claim 1,where the compound is in the form of an acetone solvate.
 7. The methodaccording to claim 6, in which the acetone solvate contains between 5%and 8% by weight of acetone.
 8. The method according to claim 1, wherethe compound is administered at a dose of between 15 and 25 mg/m², theprednisone or prednisolone being administered at a dose of 10 mg/day. 9.The method according to claim 8, where the compound is administered at adose of 25 mg/m².
 10. The method according to claim 1, comprisingrepeating the administration of such compound as a new cycle every 3weeks.
 11. The method according to claim 10, wherein the median numberof cycles is
 6. 12. The method according to claim 1, where the compoundis administered in combination with prednisone for the treatment ofpatients with castration resistant metastatic prostate cancer orhormone-refractory prostate cancer and who have been previously treatedwith docetaxel based regimen.
 13. The method according to claim 12,where the compound is cabazitaxel.
 14. The method according to claim 1,wherein said compound is administered in an amount to provide an AUC ofabout 991 ng·h/mL (CV 34%).
 15. The method according to claim 1, whereinsaid compound is administered in an amount to provide an C_(max) ofabout 226 ng·h/mL (CV 107%).
 16. The method according to claim 1 whereinsaid compound is administered in an amount to provide a plasma clearanceof 48.5 L/h (CV 39%).
 17. The method according to claim 1, furthercomprising monitoring blood counts and measuring neutrophil levels inthe patient.
 18. The method according to claim 17, wherein saidmonitoring comprises taking a blood sample from the patient.
 19. Themethod according to claim 18, further comprising discontinuingcabazitaxel treatment in a patient with a neutrophil count of ≤1,500cells/mm³.
 20. A method of reducing the risk of a severehypersensitivity reaction in a patient with prostate cancer beingtreated with a compound as defined in claim 1 comprising administeringto the patient a medication to prevent hypersensitivity prior to theadministration of cabazitaxel.
 21. A method of increasing the survivalof a patient with hormone refractory metastatic prostate cancer,comprising administering a clinically proven effective amount of acompound as defined in claim 1 to the patient in combination withprednisone or prednisolone.